5UWG

The crystal structure of Fz4-CRD in complex with palmitoleic acid

5UWG の概要

• エントリーDOI: 10.2210/pdb5uwg/pdb
• 関連するPDBエントリー: 5CL1 5CM4
• 分子名称: Frizzled-4, PALMITOLEIC ACID, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: wnt, frizzled, signalosome, cysteine-rich domain, wnt5a, wnt8, frizzled-4, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29212.70

構造登録者

Ke, J.,DeBruine, Z.J.,Gu, X.,Brunzelle, J.S.,Xu, H.E.,Melcher, K. (登録日: 2017-02-21, 公開日: 2017-06-14, 最終更新日: 2024-10-09)

主引用文献

DeBruine, Z.J.,Ke, J.,Harikumar, K.G.,Gu, X.,Borowsky, P.,Williams, B.O.,Xu, W.,Miller, L.J.,Xu, H.E.,Melcher, K.
Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization.
Genes Dev., 31:916-926, 2017

PubMed Abstract: Wnt/β-catenin signaling is activated when extracellular Wnt ligands bind Frizzled (FZD) receptors at the cell membrane. Wnts bind FZD cysteine-rich domains (CRDs) with high affinity through a palmitoylated N-terminal "thumb" and a disulfide-stabilized C-terminal "index finger," yet how these binding events trigger receptor activation and intracellular signaling remains unclear. Here we report the crystal structure of the Frizzled-4 (FZD) CRD in complex with palmitoleic acid, which reveals a CRD tetramer consisting of two cross-braced CRD dimers. Each dimer is stabilized by interactions of one hydrophobic palmitoleic acid tail with two CRD palmitoleoyl-binding grooves oriented end to end, suggesting that the Wnt palmitoleoyl group stimulates CRD-CRD interaction. Using bioluminescence resonance energy transfer (BRET) in live cells, we show that WNT5A stimulates dimerization of membrane-anchored FZD CRDs and oligomerization of full-length FZD, which requires the integrity of CRD palmitoleoyl-binding residues. These results suggest that FZD receptors may form signalosomes in response to Wnt binding through the CRDs and that the Wnt palmitoleoyl group is important in promoting these interactions. These results complement our understanding of lipoprotein receptor-related proteins 5 and 6 (LRP5/6), Dishevelled, and Axin signalosome assembly and provide a more complete model for Wnt signalosome assembly both intracellularly and at the membrane.

PubMed: 28546512
DOI: 10.1101/gad.298331.117

実験手法

X-RAY DIFFRACTION (2.56 Å)